OVERALL DESCRIPTION (Taken directly from the application) Polycystic kidney disease is observed throughout the animal kingdom. In humans it frequently leads to renal failure. It is widely believed that the destructive consequences of this group of diseases rest in the development of cysts within renal tubule segments and their growth to enormous size. The Kansas Interdisciplinary Center for PKD Research will build-on a rich history of basic and clinical polycystic kidney disease research at this site to address important questions about the molecular and cellular pathogenesis of cyst development and growth. The theme of this Center application is "Polycystin and signal transduction in polycystic kidney disease". Four established PKD investigators and one established researcher new to this field are Principal Investigators of five research projects. An administrative Core will include a pilot and feasibility study by an established molecular biologist who is new to the field. All of the projects are explicitly linked to the study of polycystic kidney disease and range from studies of polycystin mutations in lower organisms to the molecular mechanisms by which cysts develop and progressively enlarge in mammals. Lower animals serve as a road map to functions that are highly conserved in the biologic kingdom. Project 1 will determine the patterns of expression and comparative functions of two cyst-forming genes, CePKD-2 and CeTg737, in C. elegans. Project 2 will establish a model of polycystic kidney disease in Drosophila in order to reconstruct the network of molecular events in the PKD1/PKD2 mediated pathway. Project 3 will test the hypothesis that PKD1 functions as a G-protein coupled receptor that when mutated disturbs early embryological development and the development of the kidney and other organ systems. Project 4 will test the hypothesis that polycystin-1 regulates signal transduction pathways that modulate the activity of glucocorticoid receptor using the glucocorticoid-induced expression of the renal glutathione S-transferase Ya gene as a model system. Project 5 will test the hypothesis that in ADPKD, renal cyst enlargement is accelerated by elevated levels of intracellular cyclic AMP that, through the activation of protein kinase A, stimulates other cellular mechanisms, most notably the ERK/MAP kinase pathway. Project 6 will test the "second hit" hypothesis as a mechanism for the onset of polycystic kidney disease by producing mice containing both a primary mutation in PKD 1 and an inducible second-hit somatic mutation in the other allele. The long term goal is for this research to contribute to novel treatments to slow or arrest the progression of polycystic kidney disorders.